The present invention generally relates to implantable drug delivery and electrical stimulation systems and methods, and more particularly relates to utilizing one or more implantable devices to deliver electrical stimulation and/or one or more stimulating drugs as a treatment for mood and/or anxiety disorders.
Recent estimates indicate that more than 19 million Americans over the age of 18 years experience a depressive illness each year. The American Psychiatric Association recognizes several types of clinical depression, including Mild Depression (Dysthymia), Major Depression, and Bipolar Disorder (Manic-Depression). Major Depression is defined by a constellation of chronic symptoms that include sleep problems, appetite problems, anhedonia or lack of energy, feelings of worthlessness or hopelessness, difficulty concentrating, and suicidal thoughts. Approximately 9.2 million Americans suffer from Major Depression, and approximately 15 percent of all people who suffer from Major Depression take their own lives. Bipolar Disorder involves major depressive episodes alternating with high-energy periods of rash behavior, poor judgment, and grand delusions. An estimated one percent of the American population experiences Bipolar Disorder annually.
Significant advances in the treatment of depression have been made in the past decade. Since the introduction of Selective Serotonin Reuptake Inhibitors (SSRIs), e.g., Prozac(copyright) antidepressant, many patients have been effectively treated with anti-depressant medication. New medications to treat depression are introduced almost every year, and research in this area is ongoing. However, an estimated 10 to 30 percent of depressed patients taking an antidepressant are partially or totally resistant to the treatment. Those who suffer from treatment-resistant depression have almost no alternatives.
Electroconvulsive Therapy (ECT) is an extreme measure that is used today to treat such patients. In ECT, a low-frequency electrical signal is sent through the brain to induce a 30- to 60-second general seizure. The side effects include memory loss and other types of cognitive dysfunction.
Repetitive Transcranial Magnetic Stimulation (rTMS) is currently being explored as another therapy for depression. Kirkcaldie et al. (1997) reported a greater than 50 percent response rate when applying rTMS to the left dorsolateral prefrontal cortex of 17 depressed patients. In addition, a company headquartered in Houston, Tex. is currently exploring the application of vagus nerve stimulation to treatment-resistant depression; Rush, et al. (1999) report a success rate of 40-50 percent in a recent study of 30 patients.
Deep Brain Stimulation (DBS) has been applied to the treatment of central pain syndromes and movement disorders, and it is currently being explored as a therapy for epilepsy. For instance, U.S. Pat. No. 6,016,449 to Fischell, et al. discloses a system for the electrical stimulation of areas in the brain for the treatment of certain neurological diseases such as epilepsy, migraine headaches and Parkinson""s disease. However, Fischell et al. do not teach or suggest the use of such a system for the treatment of mood disorders, such as depression.
As was recently reported by Bejjani, et al. (1999), a patient responded to DBS of an area near the thalamus during the therapeutic placement of a stimulator for tremor, by lapsing into a sudden and marked depressive episode. The depression ceased within a couple of minutes after stimulation was halted, and the patient demonstrated a rebound ebullience. This phenomenon was repeated in the same patient several weeks later for purposes of verification.
New functional imaging techniques have led to the identification of several sites in the brain that demonstrate abnormal characteristics (e.g., hypoperfusion) in depression. Several regions of the brain have been identified as having decreased blood flow or metabolism in depressed patients compared to controls. In an important 1997 study, Drevets et al. reported that the subgenual prefrontal cortex (i.e., the anterior cingulate gyrus ventral to the corpus callosum) demonstrated decreased blood flow or metabolism in patients with Major Depression and with Bipolar Disorder compared with psychiatrically normal controls.
Similarly, Ebmeier et al. (1997), in a review of several studies, reported that the anterior cingulate gyrus demonstrates decreased blood flow or metabolic activity in depressed patients. In a 1999 review, Davidson et al. cite several reports that indicate that the left anterior cingulate gyrus demonstrates decreased activity in depression and furthermore demonstrates increased activity in depressed patients who respond to antidepressant medication.
Galynker et al. (1998) reported that decreased blood flow in the left dorsolateral prefrontal cortex correlated with severity of negative symptoms in depressed patients. (The left dorsolateral prefrontal cortex is the primary target of rTMS in the treatment of depression.) Drevets, in an extensive 1998 review, generalizes these results to suggest that the dorsal prefrontal cortex demonstrates decreased activity in depression while the ventral prefrontal cortex demonstrates increased activity.
Bench et al. (1992) reported decreased blood flow in the left anterior cingulate gyrus and the left dorsolateral prefrontal cortex in depressed patients as compared with controls, and further reported increased blood flow in the cerebellar vermis in depressed patients with depression-related cognitive impairment.
As stated above, Drevets reported that the ventral prefrontal cortex demonstrates increased activity in depressed patients, and further reported evidence that blood flow and metabolism are abnormally increased in the medial thalamus in patients with Major Depression and Bipolar Disorder as compared with controls. As also stated above, Bench reported abnormally increased blood flow in the cerebellar vermis in depressed patients with depression-related cognitive impairment. Abercrombie et al. (1998) reported that the metabolic rate in the right amygdala predicts negative affect in depressed patients (although no absolute difference was found between depressed and control subjects).
Recent studies of neurotransmitter receptors in the brains of patients with depression also suggest possible sites of the brain that are abnormal in depression. Stockmeier et al. (1997) reported an increased number of serotonin receptors in the dorsal raphe nucleus of suicide victims with major depression as compared with psychiatrically normal controls. Similarly, Yavari et al. (1993) reported decreased activity in the dorsal raphe nucleus in a rat model of endogenous depression. Klimek et al. (1997) reported reduced levels of norepinephrine transporters in the locus coeruleus in major depression. These findings corroborate existing anatomical evidence regarding the functions of these areas.
In 1998, Saxena et al. performed a study of the pathophysiology of obsessive-compulsive disorder. They found that at least a subgroup of patients with obsessive-compulsive disorder may have abnormal basal ganglia development. They observed that obsessive-compulsive disorder symptoms are associated with increased activity in the orbitofrontal cortex, caudate nucleus, thalamus, and anterior cingulate gyrus.
The dorsal and median raphe nuclei, which course within the medial forebrain bundle, the dorsal longitudinal fasciculus, and the medial longitudinal fasciculus, have long been known to have major serotonergic projections to the limbic system. Medications that block serotonin reuptake (thus increasing its level) are effective therapy for depression, panic disorder, obsessive-compulsive disorder, and other mood and anxiety disorders.
The locus coeruleus, which lies near the floor of the fourth ventricle, has major noradrenergic projections to virtually the entire central nervous system, including the cerebral cortex, the limbic system, and the hypothalamus. Medications that dually block serotonin and norepinephrine reuptake (and thus increase their levels) are effective therapy for depression, panic disorder, obsessive-compulsive disorder, and other mood and anxiety disorders.
Low-frequency electrical stimulation (i.e., less than 50-100 Hz), has been demonstrated to excite neural tissue, leading to increased neural activity. Similarly, excitatory neurotransmitters, agonists thereof, and agents that act to increase levels of an excitatory neurotransmitter(s) have been demonstrated to excite neural tissue, leading to increased neural activity. Inhibitory neurotransmitters have been demonstrated to inhibit neural tissue, leading to decreased neural activity; however, antagonists of inhibitory neurotransmitters and agents that act to decrease levels of an inhibitory neurotransmitter(s) have been demonstrated to excite neural tissue, leading to increased neural activity.
High-frequency electrical stimulation (i.e., more than about 50-100 Hz) is believed to have an inhibitory effect on neural tissue, leading to decreased neural activity. Similarly, inhibitory neurotransmitters, agonists thereof, and agents that act to increase levels of an inhibitory neurotransmitter(s) have an inhibitory effect on neural tissue, leading to decreased neural activity. Excitatory neurotransmitters have been demonstrated to excite neural tissue, leading to increased neural activity; however, antagonists of excitatory neurotransmitters and agents that act to decrease levels of an excitatory neurotransmitter(s) inhibit neural tissue, leading to decreased neural activity.
Various electrical stimulation and/or drug infusion devices have been proposed for treating neurological disorders. Some devices stimulate through the skin, such as electrodes placed on the scalp. Other devices require significant surgical procedures for placement of electrodes, catheters, leads, and/or processing units. These devices may also require an external apparatus that needs to be strapped or otherwise affixed to the skin.
While some patents exist that teach drug infusion and/or electrical stimulation for treatment of neurological disorders (see, e.g., U.S. Pat. Nos. 5,092,835; 5,299,569; 5,540,734; 5,975,085; 6,128,537; and 6,167,311), the inventors know of no device that targets the areas of the brain previously discussed and provides chronic stimulation via a device that is implanted completely within the head of the patient. For instance, in U.S. Pat. No. 6,128,537 (the ""537 patent), the infusion pump (reference number 10), the electrical signal generator (reference number 16), or both devices are implanted in the body of the patient, but not in the head of the patient. In the figures depicting the implanted devices (FIGS. 1, 4, 5, 6, and 7), it is readily seen that a catheter (number 22 in FIGS. 1, 4, 6, and 7) or a cable (numbered 42xe2x80x2 in FIG. 5) is tunneled through, at the very least, the neck of the patient in order to allow a drug or electrical stimulation to reach a desired target in the brain. Further, note column 6, lines 8-10 of the ""537 patent: xe2x80x9cSignal generator 16 is implanted in a human body, preferably in a subcutaneous pocket located over the chest cavity or the abdomen.xe2x80x9d There is no recognition in the ""537 patent that tunneling catheters and/or cables from the chest to the head, or from the abdomen to the head, is a problem to be overcome.
On the other hand, U.S. Pat. No. 6,167,311 (the ""311 patent) seems to recognize this problem, but offers no solution. Additionally, the ""311 patent acknowledges that there is no presently available solution, and that therefore, the signal generator xe2x80x9cmust be disposed at a remote site in the patient""s body.xe2x80x9d Note column 7, lines 57-62 of the ""311 patent: xe2x80x9cAs is readily obvious to anyone who has witnessed the unnecessary surgical procedure associated with the remote localization of the power source, it is desirable the burr cap structure itself comprise the signal source. However, as that option is not presently available the signal source generator must be disposed at a remote site in the patient""s body.xe2x80x9d
As implied by the ""311 patent, there are significant problems associated with existing systems and methods (such as in the ""537 and ""311 patents) for implanting a signal generator, infusion pump, or other device at a remote site in the patient""s body, which result in tunneling of a catheter(s) or cable(s) through the neck and other areas of the body. For instance, tunneling a long cable through the neck can easily lead to lead damage and breakage. In addition, the long cable routed through the neck to the brain provides an extended track for infection directly into the brain. Also, surgical tunneling for the cable and placement of the signal generator require general anesthesia due to the large, broad area involved. General anesthesia has a rather high risk of mortality and morbidity vis-xc3xa1-vis local anesthetic. In addition, the tunneling tool used for the long cable passes dangerously close to the common carotid artery and the jugular vein in the neck, with attendant risks of bleeding and stroke.
In addition to the above and other problems not acknowledged or addressed by the prior art, is the existence of areas in the brain of patients with mood and/or anxiety disorders with decreased activity compared with control subjects. For instance, the ""537 patent teaches treating anxiety by decreasing neuronal activity in certain areas of the brain that exhibit increased activity.
The invention disclosed and claimed herein provides systems and methods for introducing one or more stimulating drugs and/or applying electrical stimulation to one or more areas of the brain via a xe2x80x9cskull-mountedxe2x80x9d device. The stimulation may be used to treat mood and/or anxiety disorders. The findings described earlier suggest that electrical stimulation of specific sites in the brain may lead to profound changes in mood. For instance, the functional imaging and clinical studies described above suggest likely targets for Deep Brain Stimulation (DBS) as a therapy for depression.
Patients with mood and/or anxiety disorders will likely respond to therapeutic excitatory stimulation applied to those areas of the brain that exhibit chronic decreased activity relative to psychiatrically normal control subjects. Such excitatory stimulation is likely to be produced by low-frequency electrical stimulation, an excitatory neurotransmitter agonist, an inhibitory neurotransmitter antagonist, and/or a medication that increases levels of an excitatory neurotransmitter, such as Prozac(copyright) antidepressant (i.e., fluoxetine hydrochloride).
Patients with mood and/or anxiety disorders will likely respond to therapeutic inhibitory stimulation applied to those areas of the brain that exhibit chronic increased activity relative to psychiatrically normal control subjects. Such inhibitory stimulation is likely to be produced by high-frequency electrical stimulation, an inhibitory neurotransmitter agonist, an excitatory neurotransmitter antagonist, and/or a medication that increases the level of an inhibitory neurotransmitter.
The treatment provided by the invention is carried out by at least a system control unit (SCU). In one preferred form, and SCU comprises an implantable pulse generator (IPG) and implantable electrode(s) in the case of electrical stimulation only and an implantable pump and catheter(s) in the case of drug infusion only. However, an SCU preferably provides both electrical stimulation and one or more stimulating drugs when necessary and desired. In this embodiment, the SCU is preferably implanted in a surgically-created shallow depression in the temporal bone, with one or more electrode leads and/or catheters attached to the SCU running subcutaneously to an opening in the skull where they pass into or onto the brain parenchyma and surrounding tissue. In another preferred form of an SCU, a miniature implantable neurostimulator, such as a Bionic Neuron (also referred to as a BION(trademark) microstimulator), is implanted. Preferred systems also include one or more sensors for sensing symptoms or other conditions that may indicate a need for treatment.
The SCU preferably includes a programmable memory for storing data and/or control stimulation parameters. This allows stimulation and control parameters to be adjusted to levels that are safe and efficacious with minimal discomfort. Electrical and drug stimulation may be controlled independently; alternatively, electrical and drug stimulation may be coupled, e.g., electrical stimulation may be programmed to occur only during drug infusion.
A preferred form of the invention uses one or more stimulating drugs and/or electrical stimulation to treat depression. According to one embodiment of the invention, the stimulation increases excitement of one or more of those areas of the brain that exhibit chronic decreased activity in patients relative to psychiatrically normal control subjects, thereby treating or preventing depression. Such excitatory stimulation is likely to be produced by low-frequency electrical stimulation, an excitatory neurotransmitter agonist(s) (e.g., norepinephrine), an inhibitory neurotransmitter antagonist(s), and/or a medication that increases the level of an excitatory neurotransmitter (e.g., Prozac(copyright) antidepressant). Additional uses of the present invention include the application to panic disorder, obsessive-compulsive disorder, and other mood and/or anxiety disorders.
According to another embodiment of the invention, the stimulation decreases excitement of one or more of those areas of the brain that exhibit chronic increased activity in patients relative to psychiatrically normal control subjects, thereby treating or preventing depression. Such inhibitory stimulation is likely to be produced by high-frequency electrical stimulation, an inhibitory neurotransmitter agonist(s) (e.g., Gamma-Aminobutyric Acid, or GABA), an excitatory neurotransmitter antagonist(s), and/or a medication that increases the level of an inhibitory neurotransmitter. Again, additional uses include the application to panic disorder, obsessive-compulsive disorder, and other mood and/or anxiety disorders.
According to a preferred embodiment of the invention, the electrodes used for electrical stimulation are arranged as an array on a very thin implantable lead. The SCU is programmed to produce either monopolar electrical stimulation, e.g., using the SCU case as an indifferent electrode, or to produce bipolar electrical stimulation, e.g., using one of the electrodes of an electrode array as an indifferent electrode. The SCU includes a means of stimulating a nerve or infusing a stimulating drug(s) either intermittently or continuously. Specific stimulation parameters may provide therapeutic advantages for, e.g., various forms of mood and/or anxiety disorders.
The SCU used with the present invention preferably possesses one or more of the following properties:
at least two electrodes for applying stimulating current to surrounding tissue and/or a pump and at least one catheter for delivering a drug or drugs to surrounding tissue;
electronic and/or mechanical components encapsulated in a hermetic package made from biocompatible material(s);
an electrical coil inside the package that receives power and/or data by inductive or radio-frequency (RF) coupling to a transmitting coil placed outside the body, avoiding the need for electrical leads to connect devices to a central implanted or external controller;
means for receiving and/or transmitting signals via telemetry;
means for receiving and/or storing electrical power within the SCU; and
a form factor making the SCU implantable in a depression or opening in the skull.
The power source of the SCU is preferably realized using one or more of the following options:
(1) an external power source coupled to the SCU via a radio-frequency (RF) link;
(2) a self-contained power source made using any means of generation or storage of energy, e.g., a primary battery, a replenishable or rechargeable battery, a capacitor, a supercapacitor; and/or
(3) if the self-contained power source is replenishable or rechargeable, a means of replenishing or recharging the power source, e.g., an RF link, an optical link, or other energy-coupling link.
According to one embodiment of the invention, an SCU operates independently. According to another embodiment of the invention, an SCU operates in a coordinated manner with other implanted SCUs, other implanted devices, or with devices external to the patient""s body.
According to yet another embodiment of the invention, an SCU incorporates means of sensing the disorder or symptoms thereof, or other measures of the state of the patient. Sensed information is preferably used to control the electrical and/or drug stimulation parameters of the SCU in a closed loop manner. According to one embodiment of the invention, the sensing and stimulating means are incorporated into a single SCU. According to another embodiment of the invention, the sensing means communicates sensed information to at least one SCU with stimulating means.
Thus, the present invention provides systems and methods for the treatment of mood and/or anxiety disorders that utilizes at least one compact, relatively inexpensive SCU. The implant site is preferably chosen to result in a relatively simple procedure, with the associated advantages in terms of reduced surgical time, expense, possible error, and opportunity for infection. Other advantages of the present invention include, inter alia, the system""s monitoring and programming capabilities, the power source, storage, and transfer mechanisms, the activation of the device by the patient or clinician, the system""s open loop capabilities and closed loop capabilities coupled with sensing a need for and/or response to treatment, and coordinated use of one or more SCUs.